Does CBD Interact With Diphenhydramine (Benadryl)?

Diphenhydramine (DPH) is the active ingredient in the anti-allergy medication Benadryl and sleep aid Unisom.

Taking diphenhydramine with CBD (cannabidiol) can result in moderate to severe drug interaction. CBD increases the severity of the side effects of diphenhydramine while also decreasing its clearance from the system.

These two agents should not be taken together unless instructed by a physician.

Does CBD Interact With Diphenhydramine (Benadryl)?

Yes, CBD can increase blood levels of diphenhydramine (Benadryl) over time, leading to severe side effects.

Diphenhydramine is a fast-acting and readily available medication. Due to its action on the histamine receptors, the medication can produce several side effects: confusion, drowsiness, dizziness, and sedation.

CBD may inhibit the breakdown and excretion of diphenhydramine from the body, leading to elevated levels of this medication in the bloodstream. High serum blood levels of diphenhydramine are extremely dangerous.

1. Increased Effects (Agonistic Interaction)

This type of interaction refers to the increased activity or effects caused by the drug after it interacts with CBD.

CBD and other cannabinoids may enhance the sedative effects of diphenhydramine, causing severe sedation and sleepiness. This interaction is uncomfortable but can also be dangerous. Users may fall asleep suddenly while driving or operating other forms of machinery — potentially leading to injury or death.

Additionally, this level of sedation could interfere with essential responsibilities, such as monitoring small children or pets.

2. Slowed Elimination (Metabolic Competition)

Medications need to be excreted out of the system after they have produced their effects.

Drugs are excreted through urine or feces, a process that requires the metabolism of the drug first. Drug metabolism is usually the function of the liver. Almost 90 percent of all medications metabolize in the liver; it uses different enzymes and enzyme systems such as Cytochrome CYP450.

Enzyme CYP2D6 mainly metabolizes diphenhydramine [1]. It also metabolizes CBD, which could inhibit or slow the breakdown of diphenhydramine [2].

Over time, diphenhydramine could accumulate in the body, leading to dangerously high levels. People who use it daily are most at risk of this interaction.

If you use diphenhydramine every once in a while, it’s unlikely this interaction will be a significant concern. However, if you’re using it daily or in high doses, this interaction could lead to severe side effects, including delirium, sedation, or even death.

Other Names for Diphenhydramine

Diphenhydramine is sold under many different names. All share the same risk and potential interactions.

Other names for diphenhydramine include:

• Benadryl
• Unisom
• Nytol

CBD & Other Antihistamines

Diphenhydramine is classified as an antihistamine. CBD and antihistamines all share similar risks for interaction and side effects.

Here’s a list of similar medications that share an equal level of risk when combined with CBD:

• Carbinoxamine (Palgic)
• Desloratadine (Clarinex)
• Hydroxyzine (Atarax & Vistaril)
• Levocetirizine (Xyzal)
• Brompheniramine (Dimetane)
• Cetirizine (Zyrtec)
• Chlorpheniramine (Chlor-Trimeton)
• Clemastine (Tavist)
• Diphenhydramine (Benadryl)
• Fexofenadine (Allegra)
• Loratadine (Alavert & Claritin)

Is It Safe to Take CBD & Diphenhydramine Together?

No, CBD and diphenhydramine (Benadryl) are not safe to take together unless specified by a physician.

It’s important to avoid their interaction unless medically necessary.

Before combining these compounds, it’s crucial to weigh the benefits and the possible drug interaction to ensure maximal health benefits.

Is CBD a Viable Alternative to Benadryl?

No, CBD has entirely different effects and is not an alternative for diphenhydramine.

With that said, CBD does offer some mild anti-allergy benefits in the form of anti-inflammatory effects [3]. CBD is also a mild to moderate sedative that may provide support in place of diphenhydramine (Unisom) for improving sleep.

For seasonal allergies, CBD can offer direct benefits in the form of its inhibitory action on pro-inflammatory cytokines [4]. Once exposed to an allergen, the human body secretes pro-inflammatory cytokines that cause what we refer to as seasonal allergy symptoms.

These benefits take a while to work. You’re not going to be able to wake up in the morning feeling stuffy and take some CBD to clear it up. Diphenhydramine is much better for acute allergies.

However, if you know you have seasonal allergies, CBD may work as a preventative if taken consistently during allergy season.

What Is Diphenhydramine (Benadryl)?

Benadryl is the brand name for a compound called diphenhydramine (DPH). It’s an antihistamine drug and works by blocking the histamine receptors to relieve allergy symptoms, hay fever, and the common cold, such as itching, watery eyes, runny nose, and a sore throat.

Diphenhydramine is the key ingredient of Benadryl and is also available under different brand names like Unisom and Nytol. Regardless of the brand name, the chemical structure used remains the same. The medication dosage and the form, tablet, capsule, rapid dissolving pills, or syrup, differ for patients based on their age group and primary complaint.

Diphenhydramine (Benadryl) Specs:

What Does Diphenhydramine Do?

Diphenhydramine (Benadryl) targets the histamine receptors, namely H1R. These receptors are in the respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons.

The activation of H1R results in vasodilation, causing flushing and smooth muscle contractions like bronchospasms, laryngospasms, and coughing. It also stimulates the entry of neutrophils to the affected area, which is important for developing symptoms of an allergic reaction.

Diphenhydramine inhibits the H1R as an inverse agonist, meaning that it binds to the receptor’s active site where histamine would normally bind. It also inhibits the receptor, producing effects opposite to the usual effects of H1R.

Diphenhydramine belongs to the first generation antihistamines, and the main difference between first-generation and second-generation is that the former can cause drowsiness and even act as a sedative. This is because diphenhydramine and other first-generation antihistamines can cross the blood-brain barrier and act as an inverse agonist on the H1R in the brain.

Diphenhydramine is also antimuscarinic; it targets muscarinic acetylcholine M2 receptors because M2 receptors and H1 receptors are structurally similar. This antimuscarinic action of diphenhydramine on acetylcholine receptors makes the medication a potential antiparkinson medication. Parkinson’s is a disorder that alters the balance between acetylcholine and dopamine in the brain.

Diphenhydramine also is believed to affect the intracellular sodium channels, blocking their actions and producing an anesthetic effect. 

What Are the Side Effects of Diphenhydramine (Benadryl)?

Diphenhydramine (Benadryl) is a potent medication with several uses and benefits. Similarly, there are quite a few risks and complications associated with diphenhydramine use, especially if taken in combination with other medicines.

Some of the common side effects of diphenhydramine include:

• Constipation
• Dizziness
• Drowsiness
• Dry mouth, nose, and throat
• Hallucinations/delirium
• Increased chest congestion
• Loss of appetite
• Nausea
• Vomiting

When to Avoid Using Diphenhydramine (Benadryl)

Diphenhydramine (Benadryl) is an over-the-counter medication readily available to anyone with allergies or the common cold.

However, its use is not recommended for all age groups, especially older people. People over the age of 65 should only use the medication in case of a severe allergic reaction and after consulting with their primary care physicians.

Pregnant and breastfeeding women should refrain from using this medication. If used while pregnant, the person should inform their doctor immediately.

Moreover, it’s essential to avoid driving or operating heavy machinery after taking diphenhydramine as the medication is a strong sedative and can cause drowsiness. Mixing it with certain other drugs, such as other first-generation antihistamines and CBD, intensifies this drowsiness.

Key Takeaways: Is It Safe to Take Diphenhydramine With CBD?

Diphenhydramine (Benadryl) and CBD are both readily available in the United States without a prescription, but these two medications should not be used in combination — especially if taking diphenhydramine regularly.

Over time, DPH could build up in the bloodstream, leading to toxic levels. Side effects of this medication when serum levels increase can be severe — including delirium, severe somnolescence, memory loss, and death.

References Cited:

1. Akutsu, T., Kobayashi, K., Sakurada, K., Ikegaya, H., Furihata, T., & Chiba, K. (2007). Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug metabolism and disposition, 35(1), 72-78.
2. Yamaori, S., Okamoto, Y., Yamamoto, I., & Watanabe, K. (2011). Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. Drug Metabolism and Disposition, 39(11), 2049-2056.
3. Petrosino, S., Verde, R., Vaia, M., Allarà, M., Iuvone, T., & Di Marzo, V. (2018). Anti-inflammatory properties of cannabidiol, a nonpsychotropic cannabinoid, in experimental allergic contact dermatitis. Journal of Pharmacology and Experimental Therapeutics, 365(3), 652-663.
4. Vuolo, F., Abreu, S. C., Michels, M., Xisto, D. G., Blanco, N. G., Hallak, J. E., … & Dal-Pizzol, F. (2019). Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. European journal of pharmacology, 843, 251-259.